Peptic ulcer disease is manifested by ulceration of the mucous membrane of the esophagus, stomach and/or duodenum. The etiology of peptic ulcer disease remains uncertain. However, it is known that hydrochloric acid secreted by the parietal cells of the stomach is intimately involved in the disease process.
Many attempts have been made to develop drugs which inhibit gastric acid secretion or neutralize gastric contents and thus provide therapeutic utility in the treatment of peptic ulcer disease. To date, compounds which have been shown to be effective in reducing symptoms of peptic ulcer disease are those which reduce gastric acid secretion via H-2 receptor antagonism and those which, when taken in adequate amounts, are therapeutically equivalent to H-2 receptor antagonists.
In recent years, the accepted treatment for peptic ulcer disease has depended upon drugs such as antacids which neutralize gastric acid, anticholinergics and H-2 receptor antagonists which reduce acid secretion in the stomach, and drugs such as sucralfate and carbenoxolone which increase the rate of healing of peptic ulcers but do not inhibit gastric acid secretion. These latter compounds may have cytoprotective (mucoprotective) activities similar to the prostaglandins and prostaglandin analogs.
A search has been underway for a compound which has both antisecretory and cytoprotective effects. Such a combination of effects would be expected to have therapeutic utility in treatment of peptic ulcer disease and possibly other diseases of the upper gastrointestinal tract such as "stress ulcer", erosive gastritis and esophogitis; and treatment of pathological hypersecretory conditions such as Zollinger-Ellison syndrome, systemic mastocytosis and multiple endocrine adenomas, as well as limiting gastrointestinal damage associated with the use of other drugs.
In recent years, efforts to utilize imidazo[1,5-a]-pyridines to treat peptic ulcer disease and provide cytoprotective effects have not been entirely successful since such compounds have been found to exhibit only antisecretory effects.
Thus, Durant et al., in U.S. Pat. No. 4,024,271 and No. 4,228,291, disclose that certain 5,6,7,8-tetrahydroimidazo-[1,5-a]pyridines are useful in inhibiting histamine H-2 receptors and certain actions of gastrin at daily dosages of from about 150 mg. to about 1000 mg. There is no disclosure of cytoprotective activity.
Irikma et al., U.S. Pat. No. 3,790,586, disclose 3-aminoimidazo[1,5-a]pyridines with optional substituents at the 1, 5 and 7 positions which exhibit excellent gastric antisecretory action. There is no disclosure of cytoprotective activity.
Kyorin Pharmaceutical Co. Ltd., Japan 4730693-Q Sept. 11, 1972, discloses 3-acylaminoimidazo[1,5-a]pyridines, optionally substituted in the 1, 5 and 7 positions, which inhibit gastric acid secretion. There is no disclosure of cytoprotective activity.